Neurodegenerative disorders, whether caused by genetic defects, trauma, or other insults, result in long term deficits that seriously compromise the quality of life. The mechanisms that lead to neurodegeneration are complex, but recurrent themes suggest different types of neurodegenerative disorders may share common mechanisms. During the previous grant period, we made significant progress in developing two ideas: 1) that NO (nitric oxide) could be a major contributor to neuron death during ischemia, and 2) that growth factors and second messenger systems could modify the sensitivity of neurons to NO and ischemia. It is becoming increasingly clear that NO may play a central role in a number of neurodegenerative diseases, including Huntington's Chorea, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. Signalling systems that minimize the damage caused by NO have the potential are potential therapeutic agents. This application focuses both on the mechanism of NO-toxicity and on neuroprotective mechanisms. It builds on several observations from the previous grant period. We want to determine signaling pathways controlled by growth factors are protective and which gene products make neurons more resistant to NO-toxicity. We are also interested in determining the toxic events that are controlled by NO that lead to cell death. The specific aims of this grant are: Specific Aim 1. To determine the roles of the ras/MAP kinase and the rac pathways in protection against NO toxicity. Specific Aim 2(a). To understand the toxic effects of cGMP on hippocampal neurons. Specific Aim 2(b). To determine the importance of a cascade of events, including the production of cGMP, the activation of cGMP-gated non-selective cation channels (cGGCC), and the activation of the cGMP-dependent protein kinase in the sensitivity of hippocampal neurons to NO-toxicity and ischemia. Specific Aim 3. To isolate genes that encode proteins which confer resistance to NO toxicity by using an expression-cloning approach. Our long range goals are to understand the role of NO in ischemia and neurodegenerative disorders, to understand how growth factors and other signaling molecules can protect neurons from the toxic effects of NO, and to translate these discoveries into therapy.